Novel inhibitors of Chikungunya virus (CHIKV) are urgently needed to address the alarming spread of this pathogen across the Americas. The objective of this Phase I SBIR feasibility study is to identify up to 3 drug-like compound lead series that specifically and selectively inhibit CHIKV replication in cell culture. To this end, we have developed and validated a high-throughput screening assay that is suitable for compound screening against active CHIKV replication in cell culture. We will conduct a high-throughput anti-CHIKV screening campaign of a library of over 100,000 compounds with optimal drug-like properties. Quality hits that emerge from this campaign will be profiled for potency, selectivity, spectrum of activity against CHIKV and related alphaviruses, and mechanism of action. The most interesting of the compound series will undergo medicinal chemistry hit-to-lead efforts to explore structure-activity relationships (SAR). Early assessment of the oral bioavailable of representative compounds from each series will be undertaken. Success will trigger the submission of a Phase II SBIR grant that will drive chemical optimization of the series to Candidate Selection for Pre-development. Phase II will include Proof of Concept testing in animal models of CHIKV disease in the laboratory of Dr. Weaver at UTMB. The work described herein is expected to lead to the identification of one or more urgently needed inhibitor series that target Chikungunya virus.